Takeharu Kawaguchi

Clinical features of adult-onset chronic active Epstein–Barr virus infection: a retrospective analysis

We performed a retrospective analysis of patients with adult-onset chronic active Epstein–Barr virus infection (CAEBV). First, we analyzed five patients (aged 28–72) diagnosed at our hospitals with EBV-infected clonally proliferating T cells. Four patients were administered cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) chemotherapy, but no remarkable decrease of viral load was observed in three of the patients. The other patient died 19 days after initiation of CHOP treatment due to disease progression. Addition of high-dose cytarabine to the regimens of two of the patients was discontinued shortly after administration, due to the development of grade 4 pericardial effusion. Together, these regimens may be insufficient for treating adult-onset CAEBV. We next reviewed 23 adult-onset CAEBV patients, adding 18 previously reported patients to the five patients described in the present study. T cells were frequently infected (87%), whereas NK- and T-cell types are known to be almost equally prevalent in childhood-onset cases. The time duration from the onset of disease to initiation of treatment averaged 20 months. Reports showed that 12 patients died; seven patients died at an average of 8 months after initiation of treatment. Patients’ disease courses seemed to be rapidly progressive and more aggressive than those of childhood-onset cases. More cases must be studied to clarify clinical features and establish an optimal treatment strategy.

Tetraspanin CD9 modulates ADAM17-mediated shedding of LR11 in leukocytes.

LR11, also known as SorLA or SORL1, is a type-I membrane protein from which a large extracellular part, soluble LR11 (sLR11), is released by proteolytic shedding on cleavage with a disintegrin and metalloproteinase 17 (ADAM17). A shedding mechanism is presumed to have a key role in the functions of LR11, but the evidence for this has not yet been demonstrated. Tetraspanin CD9 has been recently shown to regulate the ADAM17-mediated shedding of tumor necrosis factor-α and intercellular adhesion molecule-1 on the cell surface. Here, we investigated the role of CD9 on the shedding of LR11 in leukocytes. LR11 was not expressed in THP-1 monocytes, but it was expressed and released in phorbol 12-myristate 13-acetate (PMA)-induced THP-1 macrophages (PMA/THP-1). Confocal microscopy showed colocalization of LR11 and CD9 proteins on the cell surface of PMA/THP-1. Ectopic neo-expression of CD9 in CCRF-SB cells, which are LR11-positive and CD9-negative, reduced the amount of sLR11 released from the cells. In contrast, incubation of LR11-transfected THP-1 cells with neutralizing anti-CD9 monoclonal antibodies increased the amount of sLR11 released from the cells. Likewise, the PMA-stimulated release of sLR11 increased in THP-1 cells transfected with CD9-targeted shRNAs, which was negated by treatment with the metalloproteinase inhibitor GM6001. These results suggest that the tetraspanin CD9 modulates the ADAM17-mediated shedding of LR11 in various leukemia cell lines and that the association between LR11 and CD9 on the cell surface has an important role in the ADAM17-mediated shedding mechanism.

Severe hyponatremia caused by syndrome of inappropriate secretion of antidiuretic hormone developed as initial manifestation of human herpesvirus‐6–associated acute limbic encephalitis after unrelated bone marrow transplantation

Severe hyponatremia is a critical electrolyte abnormality in allogeneic stem cell transplantation (allo‐SCT) recipients and >50% of cases of severe hyponatremia are caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Here, we present a patient with rapidly progressive severe hyponatremia as an initial sign and symptom of human herpesvirus‐6–associated post‐transplantation acute limbic encephalitis (HHV‐6 PALE) after allo‐SCT. A 45‐year‐old woman with acute lymphoblastic leukemia received unrelated bone marrow transplantation from a one locus‐mismatched donor at the DR locus. On day 21, she developed a generalized seizure and loss of consciousness with severe hyponatremia, elevated serum antidiuretic hormone (ADH), and decreased serum osmolality. A high titer of HHV‐6 DNA was detected in cerebrospinal fluid. Treatment with foscarnet sodium and hypertonic saline was started with improvement of neurological condition within several days. Although an elevated serum ADH, low serum osmolality, and high urinary osmolality persisted for 2 months, she had no other recurrent symptoms of encephalitis. Our experience suggests that hyponatremia accompanied by SIADH should be recognized as a prodromal or concomitant manifestation of HHV‐6 PALE, and close monitoring of serum sodium levels in high‐risk patients for HHV‐6 PALE is necessary for immediate diagnosis and treatment initiation.

Posterior reversible encephalopathy syndrome in an adult patient with acute lymphoblastic leukemia after remission induction chemotherapy

Posterior reversible encephalopathy syndrome (PRES) has been reported in childhood leukemia patients increasingly frequently. However, the development of PRES in adult leukemia patients during chemotherapy is very rare. We present a case of PRES in an adult patient with acute lymphoblastic leukemia (ALL) after remission induction chemotherapy. A 28-year-old woman with ALL was administered remission induction chemotherapy consisting of cyclophosphamide, daunorubicin, vincristine, prednisone, and l-asparaginase. After initiation of chemotherapy, the patient developed paralytic ileus and hypertension, and on day 30, she suddenly developed generalized convulsions, loss of visual acuity, and muscle weakness in the legs. Magnetic resonance imaging findings and her signs and symptoms were typical of PRES. The symptoms gradually improved following treatment with an anticonvulsant and an antihypertensive agent, and the patient underwent allogeneic bone marrow transplantation. She has completely recovered from PRES and has been asymptomatic without leukemia relapse. During remission induction chemotherapy for ALL, PRES may be caused by multiple drugs, such as l-asparaginase, vincristine, and corticosteroids, with different mechanisms of action. PRES should be recognized as an important complication, which will occur more frequently with the increased intensity of chemotherapy for adult ALL patients.

LR11: a novel biomarker identified in follicular lymphoma

Follicular lymphoma (FL) is the second most frequent type of non-Hodgkin lymphoma and is incurable by combination chemotherapies (Salles & Ghesquieres, 2012). Although the Follicular Lymphoma International Prognostic Index-2 (FLIPI-2) is predictive for progression-free survival (PFS) (Federico et al, 2009), widely adapted biomarkers that are directly released from FL tumour cells have not been established to date. LR11 (also called SORL1 or SorLA) is a type I membrane protein that plays a key role in the migration of undifferentiated vascular smooth muscle cells (Jiang et al, 2008), and circulating soluble LR11 (sLR11) is a biomarker for coronary stenosis (Takahashi et al, 2010). The potent action of sLR11 is mediated by the urokinase-type plasminogen activator receptor (uPAR)/integrin-mediated activation of focal adhesion kinase (FAK)/ERK/Rac1 cascades (Ohwaki et al, 2007). LR11 is also expressed in human CD34CD38 immature haematopoietic precursors (Zhang et al, 2000), but little is known about its potential role in haematopoietic cells. We have recently found that LR11 is highly expressed in leukaemic cells and that serum sLR11 levels in acute leukaemia patients are significantly increased at diagnosis and normalize at remission (Sakai et al, 2012). Here we analysed the expression profile of LR11 in FL cells and evaluated the clinical importance of serum sLR11 levels in FL patients. Tumour specimens and serum samples were collected from 61 newly diagnosed, untreated FL patients attending Chiba University Hospital and affiliated hospitals between 2002 and 2012. Fifty-two patients (85.2%) were treated with the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) regimen, 3 (4.9%) with irradiation only, and 6 (9.8%) were observed without treatment (see Table SI for patients’ characteristics). Paired serum samples at diagnosis and remission were obtained in 20 patients. Normal controls were serum samples collected from 75 healthy adult volunteers who had given informed consent.

Factors associated with the efficiency of PBSC collection in POEMS syndrome patients undergoing autologous PBSC transplantation

Factors associated with the efficiency of PBSC collection in POEMS syndrome patients undergoing autologous PBSC transplantation

Mobilization of PBSCs in poor mobilizers with POEMS syndrome using G-CSF with plerixafor

Auto-SCT has been established as an effective treatment for patients with hematological malignancies such as lymphoma or myeloma. Unfortunately, some patients fail to mobilize a sufficient number of PBSCs for transplantation. Plerixafor is the first molecule to reversibly inhibit the binding of chemokine stromal cell-derived factor-1α (SDF-1α) to its cognate receptor, CXCR4.1 Many recent reports have shown that there is a potential clinical application for plerixafor in PBSC harvesting.2, 3, 4, 5, 6

Circulating LR11 is a novel soluble-receptor marker for early-stage clinical conditions in patients with non-Hodgkin's lymphoma

BACKGROUND We reported that the soluble LDL receptor relative with 11 ligand-binding repeats (sLR11) is a promising biomarker for follicular lymphoma (FL). In this study, we evaluated the fluctuations in serum sLR11 levels compared with those of serum soluble urokinase-type plasminogen activator receptor (suPAR) and soluble interleukin-2 receptor (sIL-2R) in patients with non-Hodgkins lymphoma (NHL). METHODS Serum sLR11, suPAR, and sIL-2R levels were measured using ELISA in 175 NHL patients and 57 healthy controls. The levels at diagnosis and at remission were evaluated in 64 paired samples. RESULTS Serum sLR11 levels were significantly increased in FL, diffuse large B-cell lymphoma (DLBCL), and peripheral T-cell lymphoma patients compared with healthy controls. Serum sLR11 levels revealed significant positive correlations with serum suPAR and sIL-2R levels. Serum sLR11 levels at remission were decreased compared with those at diagnosis, and the declines at remission expressed a slope of approximately -1 with an intercept near that of controls. The receiver operating characteristic-area under the curve of serum sLR11 concentrations was equivalent to that of serum suPAR and sIL-2R concentrations in an early-stage DLBCL and FL. CONCLUSIONS sLR11 may be a novel soluble receptor indicative of early-stage NHL, with potential use for evaluating therapeutic efficacy.

Low-dose trimethoprim-sulfamethoxazole for Pneumocystis jiroveci pneumonia prophylaxis after allogeneic hematopoietic SCT.

Low-dose trimethoprim–sulfamethoxazole for Pneumocystis jiroveci pneumonia prophylaxis after allogeneic hematopoietic SCT

Potential utility of serum soluble LR11 as a diagnostic biomarker for intravascular large B-cell lymphoma

1Department of Hematology, Chiba University Hospital, Chiba, Japan, 2Department of Pathology, Saitama Medical Center, Saitama Medical University, Saitama, Japan, 3Department of Hematology, Chibaken Saiseikai Narashino Hospital, Chiba, Japan, 4Department of Hematology/Oncology, Kameda Medical Center, Chiba, Japan, 5Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan and 6Department of Clinical Laboratory and Medicine, Toho University Medical Center Sakura Hospital, Chiba, Japan